I am interested in determining the molecular and cellular mechanisms underlying  brain plasticity in development and adulthood, in health and disease.  My strategy for approaching this fundamental biological question is to start with genes, which when mutated affect plasticity, ultimately leading to neurological diseases.

Currently, I am exploring how deletion of MECP2, an X-linked gene, results in Rett Syndrome, an Autism-associated disorder. Although many mouse models of Rett Syndrome have been established, it has been difficult to identify primary molecular and cellular changes and trace their impact on circuit alterations that underlie behavioral deficits. In particular, studies in female mouse models of this disorder are sparse, though Rett Syndrome primarily affects girls and women.

Based on our emerging hypothesis that neurodevelopmental disorders may be caused by sensory processing defects, my approach is to identify the relevant conceptual paradigms and use integrated approaches at the molecular, cellular, physiological and behavioral levels to study pathogenesis of Rett Syndrome.  Our tools include genome-wide profiling of chromatin and transcriptome, fluorescent in situ hybridization, confocal microscopy, organotypic slice work, gene gun transfections, slice physiology and mouse behavior.  I believe that our research program has the potential to answer some of the basic questions regarding the function of MECP2 in experience-dependent plasticity, which is critical for neural circuit wiring, and will provide fresh mechanistic insights into the pathogenic mechanisms of Rett Syndrome.

For the long term, I am interested in identifying and generating relevant animal models for other neurodevelopmental disorders, such as Autism Spectrum Disorder, using emerging genome editing technologies such as CRISPR.

Krishnan K*$, Lau BYB*, Ewall G, Huang ZJ, Shea SD. “MECP2 regulates cortical plasticity underlying a learned behavior in adult female mice”. Manuscript in review, Nature Communications. Preprint available at bioRxiv doi: http://dx.doi.org/10.1101/041707. $-Corresponding author. *-Equal contribution

Krishnan K*, Wang BS*, Lu J, Wang L, Maffei A, Cang J, Huang ZJ. “MECP2 regulates the timing of critical period plasticity that shapes functional connectivity in the primary visual cortex.” PNAS 2015, August 25, vol. 112 no. 34 E4782-E4791. * – Equal contribution

Krishnan N, Krishnan K, Connors CR, Choy MS, Page R, Peti W, Van Aelst L, Shea SD, Tonks NK. “PTP1B inhibition suggests a therapeutic strategy for Rett Syndrome”. Journal of Clinical Investigation 2015; 125(8):3163-3177.

Lazarus MS, Krishnan K, Huang ZJ. “GAD67 deficiency in Parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex.” Cerebral Cortex, 2015; 25 (5):1290-1296, first published online November 24, 2013.

Krishnan K, Salomonis N, Guo S. “Identification of Spt5 target genes in zebrafish development reveals its dual activity in vivo,” PLoS ONE, 2008. 3(11): e3621.

Shen W, Chrobak D, Krishnan K, Lawrence HJ, Largman C. “HOXB6 protein is bound to CREB-binding protein and represses globin expression in a DNA binding-dependent, PBX interaction-independent process,” Journal of Biological Chemistry. 279(38):39895-904. 2004